The high-risk study of healthy adolescent offspring of bipolar parents has identified a potential vulnerability marker in the at- risk population. The high-risk group shows supersensitivity to the inhibitory effects of light on plasma melatonin, suggesting that this finding may represent a genetic vulnerability marker for affective disorder. We have completed a study of cholinergic induction of rapid eye movement (REM) sleep in euthymic unmedicated bipolars. The bipolars showed more rapid induction of REM sleep than did matched controls, confirming previous observations and providing additional evidence that cholinergic supersensitivity may be a genetic vulnerability marker for affective disorder. Studies of the growth hormone response to clonidine in euthymic unmediated bipolars suggest that this response is blunted in bipolar subjects compared to controls. The possibility that this represents a genetic vulnerability marker is currently being evaluated. Studies of CSF neuropeptides in normal monozygotic and dizygotic twins have shown that neuropeptide Y levels are heritable, are high in underweight anorectics and are normal in depressives. Additionally, the related neuropeptide, peptide YY, is elevated in CSF from bulimic subjects. Galanin levels in CSF are normal in Alzheimer's Disease, depression and eating disorders. Acute IV administration of physostigmine produces increases in CSF neuropeptide Y, in both monkeys and man, indicating that pharmacologic challenges may employ CSF neuropeptide levels in assessing the drug effect on various CNS neurotransmitters.